Tobian A, Serwadda D, Quinn T, et al. Male circumcision for the prevention of HSV-2 and HPV infections and syphilis. N Engl J Med 2009;360:1298-309.
Observational studies of the effect of male circumcision on the incidence of herpes simplex virus type 2 (HSV-2), human papillomavirus (HPV) and syphilis have had inconclusive results.(1,2,3,4,5) Three clinical trials have demonstrated the efficacy of male circumcision on reducing the acquisition of HIV and in one of these studies circumcised men reported less genital ulcer disease.(6,7,8) Syphilis and HSV-2 were found to be associated with an increased risk of HIV in observational studies(9) and some HPV genotypes are associated with genital cancers.(10)
To measure the efficacy of male circumcision for the prevention of HSV-2 and HPV infections and syphilis in adolescent boys and men using data obtained from a clinical trial of the efficacy of male circumcision on HIV incidence
Two parallel, independent, randomized controlled intervention trials
HIV-negative boys and men aged 15-49 years who accepted voluntary HIV testing and received their test results (Rakai-1 trial) and 595 HIV-negative boys and men of whom 155 declined to receive test results (Rakai-2)
New HSV-2, HPV, and syphilis infections
In both studies participants were randomly assigned using computer-generated random group assignments into either immediate circumcision or delayed circumcision at 24 months. Circumcised participants were followed up post-surgery for complications. All participants were followed up at four to six weeks and six, 12, and 24 months post-enrollment. Participants were tested for HIV, HSV-2, and syphilis at six, 12, and 24 months and for HPV at 24 months.
The Kaplan-Meier method was used to estimate the time to HVS-2 or syphilis seropositivity with data censoring at the last visit. An intention-to-treat analysis was performed with adjustment for baseline characteristics using the Cox proportional hazards model. A secondary analysis included adjustments for changes in the number of sexual partners, condom use, alcohol use at the time of intercourse, and symptoms of sexually transmitted diseases. A crossover as-treated analysis in which participants in the control group as well as participants in the intervention group who did not have immediate circumcision but underwent surgery at a later date were treated according to actual status. Poisson regression was used to estimate incidence-rate ratios for prevalence and 95% confidence intervals.
Rakai-1 participants were enrolled from September 2003 through September 2005 and Rakai-2 participants were enrolled from February 2004 through December 2006. In the two trials 6396 participants initially were screened of whom 3003 were excluded because of pre-existing HSV-2 or HIV infection. Enrolled were 3393 HIV-negative, HSV-2-negative uncircumcised subjects, of whom 1684 had been randomized to immediate male circumcision (intervention arm) and 1709 to male circumcision 24 months later (control arm). Retention at 24 months was 82% in both groups.
At 24 months in the intention-to-treat population, HSV-2 infection was detected in 114 subjects in the intervention group and in 153 subjects in the control group. The cumulative probability of HSV-2 infection during the 24-month period was lower in the intervention group (7.8%) than in the control group (10.3%), with an unadjusted hazard ratio of 0.75 (95% confidence interval [CI]: 0.60-0.94; P=0.02). After adjustment for enrollment characteristics and rates of sexual practices and symptoms of sexually transmitted infections, the hazard ratio was 0.72 (95% CI: 0.56-0.92; P=0.008). After adjustment for time-varying covariates during follow-up, the hazard ratio was 0.77 (95% CI: 0.62-0.97; P=0.03). In the as-treated analysis, the unadjusted hazard ratio for detection of infection was 0.73 (95% CI: 0.59 to 0.93; P=0.01); after adjustment for baseline characteristics, the hazard ratio was 0.72 (95% CI: 0.59 to 0.91; P=0.009). In separate analyses of data from the Rakai-1 and Rakai-2 trials, male circumcision reduced the incidence of HSV-2 infection in both trials.
The incidence of HSV-2 infection was lower among circumcised subjects, and there were no significant differences in the hazard ratios in subgroup analyses. Subjects who reported symptoms of sexually transmitted infections had a higher incidence of HSV-2 infection than asymptomatic subjects. At 24 months, the cumulative prevalence rates of self-reported symptoms of genital ulcer disease were higher among subjects with HSV-2 seroconversion (10.3%) than among subjects without seroconversion (2.7%) (relative risk 3.78; 95% CI: 2.87-4.98; P<0.001).
At 24 months, syphilis was detected in 50 of 2083 subjects (2.4%) in the intervention group, as compared with 45 of 2143 subjects (2.1%) in the control group (hazard ratio 1.14; 95% CI: 0.77-1.75; P=0.50). Adjustment for enrollment characteristics and rates of sexual practices and symptoms of sexually transmitted infections did not significantly affect the results.
Male circumcision reduces the risk of HSV-2 incidence and prevalence of HPV.
This was a high quality study: allocation was random and concealed, loss to follow-up was accounted for and was acceptable, and intention-to-treat (and as-treated) analyses were performed. Blinding of the intervention was not possible.
The programmatic implications of this study are great. The results of this study provide definitive evidence of the protective effect of male circumcision on acquisition of HSV-2 and HPV, in addition to the already established efficacy of male circumcision at preventing acquisition of HIV. Efforts to increase the availability of male circumcision in resource-constrained areas should be prioritized.
- Weiss HA, Buvé A, Robinson NJ, et al. The epidemiology of HSV-2 infection and its association with HIV infection in four urban African populations. AIDS 2001;15:Suppl 4:S97-S108.
- Lavreys L, Rakwar JP, Thompson ML, et al. Effect of circumcision on incidence of human immunodeficiency virus type 1 and other sexually transmitted diseases: a prospective cohort study of trucking company employees in Kenya. J Infect Dis 1999;180:330-6.
- Gray R, Azire J, Serwadda D, et al. Male circumcision and the risk of sexually transmitted infections and HIV in Rakai, Uganda. AIDS 2004;18:2428-30.
- Baldwin SB, Wallace DR, Papenfuss MR, et al. Human papillomavirus infection in men attending a sexually transmitted disease clinic. J Infect Dis 2003;187:1064-70.
- Shin HR, Franceschi S, Vaccarella S, et al. Prevalence and determinants of genital infection with papillomavirus, in female and male university students in Busan, South Korea. J Infect Dis 2004;190:468-76.
- Gray RH, Kigozi G, Serwadda D, et al. Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial. Lancet 2007;369:657-66.
- Bailey RC, Moses S, Parker CB, et al. Male circumcision for HIV prevention in young men in Kisumu, Kenya: a randomized controlled trial. Lancet 2007;369:643-56.
- Auvert B, Taljaard D, Lagarde E, Sobngwi-Tambekou J, Sitta R, Puren A. Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: the ANRS 1265 Trial. PLoS Med 2005;2(11):e298. [Erratum, PLoS Med 2006;3(5):e298.]
- Serwadda D, Gray RH, Sewankambo NK, et al. Human immunodeficiency virus acquisition associated with genital ulcer disease and herpes simplex virus type 2 infection: a nested case-control study in Rakai, Uganda. J Infect Dis 2003;188:1492-7.
- de Sanjosé S, Diaz M, Castellsagué X, et al. Worldwide prevalence and genotype distribution of cervical human papillomavirus DNA in women with normal cytology: a meta-analysis. Lancet Infect Dis 2007;7:453-9.